This invention relates to chlorinating then brominating a substituted phenol. In particular, it relates chlorinating salicylaldehyde (SAL) to form 5-chlorosalicylaldehyde (5CSAL), followed by brominating to form 3-bromo-5-chlorosalicylaldehyde (BCSAL).
BCSAL is an important intermediate used to make anti-cancer drugs. It is made by chlorinating SAL to form 5CSAL, followed by brominating the 5CSAL. The chlorination step has been performed neat (U.S. Pat. No. 3,621,064), in acetic acid (Chemische Beuchte, 37, 4 to 24,1904), and in chloroform (J. Org. Chem. 25, 546,1960). The bromination step in acetic acid is briefly mentioned in Smirnor, Kivichenko; Dokl. Chem. (Eng. Transl.) 179, 240, 1968). Results using prior art processes are less than satisfactory.
We have discovered that if SAL is chlorinated in a solvent of benzotrifluoride (BTF) a higher yield and an excellent purity are obtained after a simple workup. We have obtained yields of 75% and purities of over 99%. We have further found that if the bromination step is performed in a mixture of acetic acid and a strong base of a weak acid salt, such as sodium acetate, the formation of diaryl ethers, a major byproduct in the bromination reaction, is inhibited. We have obtained yields of 93% and purities of over 99.5% in the bromination step without further purification.
In the process of this invention, 2-bromo-4chloro substituted phenols are made in two steps. The first step is the chlorination of a substituted phenol to make a 4-chloro substituted phenol and the second step is the bromination of the 4-chloro substituted phenol. The overall general reaction, using sodium acetate and bromine, is as follows: 
The substituted phenol has the general formula shown in the above reaction, where R is CHO, COCl, or CO2Rxe2x80x3, Rxe2x80x3 is alkyl from C1 to C4, each Rxe2x80x2 is independently selected from alkyl from C1 to C4, m is 0 or 1, and n is 0 or 1. Preferably, R is CHO, Rxe2x80x2 is hydrogen, Rxe2x80x3 is hydrogen, m is 0, and n is 0 as those compounds are commercially more important. Examples of compounds that can be used include SAL, phenol, and 2-chlorophenol; SAL is preferred as it is used to make BCSAL.
The substituted phenol is mixed with BTF to form a solution. The weight ratio of BTF to the substituted phenol should be about 2 to about 4 as the product may precipitate at a lower ratio and a higher ratio will reduce the throughput and may reduce the yield; the preferred weight ratio is about 2.5 to about 3.5.
Chlorine gas is sparged into the solution. About 1 to about 1.5 equivalents of chlorine gas should be used as more may result in higher chlorinated products and less will leave unreacted substituted phenol. The preferred amount of chlorine gas is about 1.1 to about 1.2 equivalents. The reaction is exothermic and can be started at room temperature. The temperature can then be permitted to rise to about 50 to about 80xc2x0 C. The reaction is slow at lower temperatures and higher temperatures may produce more byproducts; the preferred temperature range is about 50 to about 60xc2x0 C. The reaction can be followed by performing gas chromatography (GC) on samples or by checking the amount of chlorine gas feed. When the reaction is complete, the 4-chloro substituted phenol is isolated. If the product is 5CSAL, the mixture can be cooled to about 50xc2x0 C., which precipitates the 5CSAL. The 5CSAL can then be isolated by, for example, filtration. High purity (GC greater than 99%) product can be obtained after washing twice with BTF.
In the bromination step, the 4-chloro substituted phenol is mixed with acetic acid and a salt of a strong base and a weak acid. The weight ratio of acetic acid to the 4-chloro substituted phenol is about 1 to about 5 as more acetic acid will reduce throughput and, if less is used, the mixture will be hard to stir; the preferred weight ratio is about 2 to about 3. Examples, of salts of a strong base and a weak acid that can be used include sodium acetate, potassium acetate, sodium carbonate, sodium phosphate, and sodium oxalate. The preferred salt is sodium acetate because it works well and produces additional acetic acid when it reacts. About 1 to about 2 equivalents of the salt should be used as less will result in less conversion and more is unnecessary.
Brominating agents that can be used include liquid bromine, a mixture of hydrogen bromide and hydrogen peroxide in an equimolar ratio or a mixture of hydrogen bromide and sodium hypochlorite in an equimolar ratio. The preferred brominating agent is liquid bromine as it has been found to work well. About 1 to about 1.5 equivalents of the brominating agent should be used as less will result in incomplete conversion and more may result in overbromination. Preferably, about 1.05 to about 1.2 equivalents of the brominating agent are used.
The bromination reaction is exothermic and cooling is usually necessary. The temperature should be kept below about 35xc2x0 C. to prevent overbromination. A temperature of about 25 to about 35xc2x0 C. is preferred. The reaction can be followed by analyzing samples using GC. When the reaction is complete, water can be added, which will precipitate the brominated product. The mixture can be cooled to about 5xc2x0 C. and the product can be collected by, for example, filtration, then washed with water to remove any acetic acid. The purity of the product is usually over 99%.